ABSTRACT/SUMMARY OF WORK As the most abundant immune cells residing in terminal airways, alveolar macrophages (AMs) play critical roles in lung homeostasis and respiratory function. AMs efficiently clear the air spaces of dead cells, surfactants, and pathogens, orchestrate pulmonary immune responses and tolerance, modulate tissue damage, regulate lung fibrosis, and are involved in lung cancer progression. Absence of AMs or impaired AM function can lead to abnormal accumulation of surfactants and dead cells that can promote the development of pulmonary alveolar proteinosis and inflammation, respectively. Mechanisms underlying AM development, maintenance, and function remain poorly understood; however emerging evidence suggests a role for TSC1/2 proteins. TSC1/2 are key regulators of mTOR signaling to control diverse processes such as cell metabolism, growth, proliferation, differentiation, quiescence, stemness, and autophagy. TSC1, TSC2, and TBC1D7 form the core of the TSC protein complex. Mutations in either TSC1 or TSC2 genes can lead to tuberous sclerosis (TSC), a multisystem genetic disease that causes benign tumors and other pathologic conditions in many vital organs. Strikingly, up to 49% of TSC patients manifest lung pathology, which contributes to significant disease morbidity and mortality due to lack of targeted treatment. In addition, about 1/3 of TSC patients carry inherited mutations of TSC1/2, with the potential to impact all cells including AMs and other immune cells to affect various conditions associated with TSC. However, current gaps in knowledge include the specific roles of AMs in TSC pathogenesis and how deficiency of TSC1/2 may impact AMs. To fill these gaps, the proposed project will focus on investigating how TSC1 deficiency may affect AMs to influence lung functions. Recently, we and others have demonstrated that mTORC1 is central to the homeostatic self-renewal of AMs via mediating GM- CSF induced cell cycle entry, nutrient uptake, and proliferation, which in turn ensures normal function of the lung in mice. Therefore, we will investigate how TSC1 critically controls AM homeostasis and function to ensure proper lung function via tight regulation of mTOR signaling. Our studies are expected to provide important insight into how TSC1 deficiency affects AMs, improve the understanding of TSC pathogenesis and illustrate novel TSC1-medited mechanisms that control AMs and lung function. Collectively, these results should lead to the identification and development of novel therapeutic strategies for TSC patients.